A novel role of the CX(3)CR1/CX(3)CL1 system in the cross-talk between CLL cells and tumor microenvironment

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BlankA novel role of the CX(3)CR1/CX(3)CL1 system in the cross-talk between

chronic lymphocytic leukemia cells and tumor microenvironment.

E Ferretti, M Bertolotto, S Deaglio, C Tripodo, D Ribatti, V Audrito, F Blengio,

S Matis, S Zupo, D Rossi, L Ottonello, G Gaidano, F Malavasi, V Pistoia, and A

Corcione

Leukemia, May 6, 2011;

Laboratory of Oncology, IRCCS G. Gaslini, Genova, Italy.

Several chemokines/chemokine receptors such as CCR7, CXCR4 and CXCR5 attract

chronic lymphocytic leukemia (CLL) cells to specific microenvironments. Here we

have investigated whether the CX(3)CR1/CX(3)CL1 axis is involved in the

interaction of CLL with their microenvironment. CLL cells from 52 patients

expressed surface CX(3)CR1 and CX(3)CL1 and released constitutively soluble

CX(3)CL1. One third of these were attracted in vitro by soluble CX(3)CL1.

CX(3)CL1-induced phosphorylation of PI3K, Erk1/2, p38, Akt and Src was involved

in induction of CLL chemotaxis. Leukemic B cells upregulated CXCR4 upon

incubation with CX(3)CL1 and this was paralleled by increased chemotaxis to

CXCL12. Akt phosphorylation was involved in CX(3)CL1-induced upregulation of

CXCR4 on CLL. In proliferation centers from CLL lymph node and bone marrow,

CX(3)CL1 was expressed by CLL cells whereas CX(3)CR1 was detected in CLL and

stromal cells. Nurselike cells (NLCs) generated from CLL patient blood

co-expressed surface CX(3)CR1 and CX(3)CL1, but did not secrete soluble

CX(3)CL1. Only half of NLC cell fractions were attracted in vitro by CX(3)CL1.

In conclusion, the CX(3)CR1/CX(3)CL1 system may contribute to interactions

between CLL cells and tumor microenvironment by increasing CXCL12-mediated

attraction of leukemic cells to NLC and promoting directly adhesion of CLL cells

to NLC.Leukemia advance online publication, 6 May 2011; doi:10.1038/leu.2011.88.

PMID: 21546901